Mixed Phenotype Acute Leukemia Research Articles

Mixed-phenotype leukemia with TCF3::ZNF384 fusion presenting as an isolated mediastinal mass.

Acute leukemia with TCF3::ZNF384 is a distinct type of acute leukemia that present most commonly as B-acute lymphoblastic leukemia or mixed-phenotype acute leukemia (B/myeloid). We report the first case of TCF3::ZNF384 mixed-phenotype leukemia presenting as isolated extramedullary disease in the mediastinum. Diagnosis using RNA-sequencing and whole genome sequencing on the primary issue is illustrated.

Single-cell transcriptional mapping reveals genetic and non-genetic determinants of aberrant differentiation in AML.

In acute myeloid leukemia (AML), genetic mutations distort hematopoietic differentiation, resulting in the accumulation of leukemic blasts. Yet, it remains unclear how these mutations intersect with cellular origins and whether they converge upon similar differentiation patterns. Single-cell RNA sequencing (scRNA-seq) has enabled high-resolution mapping of the relationship between leukemia and normal cell states, yet this application is hampered by imprecise reference maps of normal hematopoiesis and small sample sizes among patient cohorts. As a first step we constructed a reference atlas of human bone marrow hematopoiesis from 263,519 single-cell transcriptomes spanning 55 cellular states, that was benchmarked against independent datasets of immunophenotypically pure hematopoietic stem and progenitor cells. Using this reference atlas, we mapped over 1.2 million single-cell transcriptomes spanning 318 AML, mixed phenotype acute leukemia (MPAL), and acute erythroid leukemia (AEL) samples. This large-scale analysis, together with systematic mapping of genotype-to-phenotype associations between driver mutations and differentiation landscapes, revealed convergence of diverse genetic alterations on twelve recurrent patterns of aberrant differentiation in AML. This included unconventional lymphoid and erythroid priming linked to RUNX1 and TP53 mutations, respectively. We also identified non-genetic determinants of AML differentiation such as two subgroups of KMT2A-rearranged AML that differ in the identity of their leukemic stem cells (LSCs), likely reflecting distinct cellular origins. Furthermore, distinct LSC-driven hierarchies can co-exist within individual patients, providing insights into AML evolution. Together, precise mapping of normal and malignant cell states provides a framework for advancing the study and disease classification of hematologic malignancies thereby informing therapy development.

Breast relapse of myeloid sarcoma and SARS-CoV-2 infection following hematopoietic stem cell transplantation in mixed-phenotype acute leukemia: a case report

Abstract Background Mixed-phenotype acute leukemia is a rare, high-risk subtype of acute leukemia. Myeloid sarcoma is a localized tumor formed by the proliferation and infiltration of primitive or immature myeloid cells outside the bone marrow. It is often an extramedullary manifestation of acute myeloid leukemia, and imaging lacks specificity, leading to potential misdiagnosis. Case Presentation A female patient diagnosed with mixed-phenotype acute leukemia achieved complete remission after chemotherapy and allogeneic hematopoietic stem cell transplantation. However, a relapse occurred in the breast after transplantation. The patient achieved local control through mastectomy and removal of the axillary lymph nodes on the affected side. Unfortunately, during the subsequent course of chemotherapy, the patient died of a severe pulmonary infection caused by coronavirus disease 2019. Conclusion Continuous treatment and monitoring of mixed-phenotype acute leukemia patients are essential, especially for those with extramedullary manifestations (such as breast involvement).

Hematopoietic stem cell transplantation activity in China 2022-2023. The proportions of peripheral blood for stem cell source continue to grow: a report from the Chinese Blood and Marrow Transplantation Registry Group.

Over past two years, a total of 39,918 hematopoietic stem cell transplantation (HSCT) cases were reported, with 18,194 and 21,714 transplants performed in 2022 and 2023, respectively. Autologous HSCT accounted for 6562 cases (31%) in 2022, while allogeneic HSCT comprised 12,632 cases (69%). In 2023, the number of allogeneic HSCTs exceeded 15,000, maintaining a 69% share. Participation in the 2022 and 2023 surveys included 193 and 212 transplantation teams, respectively, from 27 provinces, municipalities, or autonomous regions. The leading indication of HSCT was acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and mixed phenotype acute leukemia, with a total of 17,421 cases. AML was the most common disease (10,339, 38%) for allogeneic HSCT, which was followed by ALL (5925 cases, 21%). Peripheral blood emerged as the primary source of stem cell grafts, utilized in 54% of matched sibling donor transplants and 77% of haploidentical donor transplants. The BuCy-based conditioning regimen was the most prevalent, used in 53% of allogeneic HSCT cases in the past two years. This survey offers a comprehensive overview of the current HSCT landscape and serves as a valuable resource for clinical practice.

Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.

Mixed-Phenotype Acute Leukemia; T/Megakaryoblastic: Does It Really Exist?

Mixed-Phenotype Acute Leukemia; T/Megakaryoblastic: Does It Really Exist?

Genetic evidence for predisposition to acute leukemias due to a missense mutation (p.Ser518Arg) in ZAP70 kinase: a case-control study

BackgroundThe apparent lack of additional missense mutations data on mixed-phenotype leukemia is noteworthy. Single amino acid substitution by these non-synonymous single nucleotide variations can be related to many pathological conditions and may influence susceptibility to disease. This case-control study aimed to unravel whether the ZAP70 missense variant (rs104893674 (C > A)) underpinning mixed-phenotype leukemia.MethodsThe rs104893674 was genotyped in clients who were mixed-phenotype acute leukemia-, acute lymphoblastic leukemia- and acute myeloid leukemia-positive and matched healthy controls, which have been referred to all major urban hospitals from multiple provinces of country- wide, IRAN, from February 11’ 2019 to June 10’ 2023, by amplification refractory mutation system-polymerase chain reaction method. Direct sequencing for rs104893674 of the ZAP70 gene was performed in a 3130 Genetic Analyzer.ResultsWe found that the AC genotype of individuals with A allele at this polymorphic site (heterozygous variant-type) contribute to the genetic susceptibility to acute leukemia of both forms, acute myeloid leukemia and acute lymphoblastic leukemia as well as with a mixed phenotype. In other words, the ZAP70 missense variant (rs104893674 (C > A)) increases susceptibility of distinct cell populations of different (myeloid and lymphoid) lineages to exhibiting cancer phenotype. The results were all consistent with genotype data obtained using a direct DNA sequencing technique.ConclusionOf special interest are pathogenic missense mutations, since they generate variants that cause specific molecular phenotypes through protein destabilization. Overall, we discovered that the rs104893674 (C > A) variant chance in causing mixed-phenotype leukemia is relatively high.

Clinicopathological differences between T-lymphoblastic leukemia/lymphoma, early T-precursor lymphoblastic leukemia/lymphoma, and mixed-phenotype acute leukemia with T lineage: An analysis of 41 adult cases

The histopathological diagnosis of T-lymphoblastic leukemia/lymphoma, NOS (T-ALL), is based on morphology and positivity for CD3 and TdT. Early T-precursor lymphoblastic leukemia/lymphoma (ETP-ALL) and mixed-phenotype acute leukemia (MPAL), T/M, and/or B rarely occur and are usually diagnosed using flow cytometry. Using only formalin-fixed paraffin-embedded tissue raises the risk of misdiagnosis due to underestimation. Immunostaining markers for T cell (CD1a, CD4, CD5, CD8), B cell (CD19, CD10, CD22, CD79a), and stem/myeloid-related cell (CD33, CD34, CD117, MPO, lysozyme) diagnosed 25 T-ALL cases (61%), 7 MPAL (17%), 6 ETP-ALL (15%), and 3 near ETP-ALL (7%), with subsequent analysis of their clinicopathological characteristics. Patients with MPAL had significantly poorer 2-year progression-free survival (14.3% vs. 60.4%, P = 0.012) and 5-year overall survival (28.6% vs. 65.9%, P = 0.011) than did those with T-ALL, whereas ETP-ALL and near ETP-ALL did not. Of the seven patients with MPAL, three were classified as T/B, two as T/M, and two as T/M/B. Because most MPALs (6/7) share the ETP-ALL phenotype, immunohistochemistry for CD19 and MPO should be performed to avoid misdiagnosing MPAL as ETP-ALL. All three patients with TdT-negative MPAL died of the disease. Four patients with MPO-positive MPAL relapsed during the early phase (1–9 months). Five patients received the ALL regimen, but two patients received acute myeloid leukemia and lymphoma regimens, respectively. In this study, MPAL exhibited a poorer prognosis compared to T-ALL, unlike ETP-ALL. Thus, immunohistochemical classification with multiple antibody panels is useful for accurate diagnosis and treatment.

Clinicohematological profile and immunophenotypic patterns of childhood acute leukemia: Prognostic correlation

Acute leukemia (AL) presents a heterogeneous molecular profile, requiring precise diagnostic categorization and subcategorization. The present study aims to estimate the clinicohematological profile and immunophenotypic pattern of childhood AL while conducting prognostic assessments. This cross-sectional study analyzed a total of 68 samples of AL collected from January 2019 to June 2021. The male-to-female ratio was 4.6:1, with a mean age of 6.6 ± 3.4 years. Total leukocyte count (TLC) was significantly increased in all types of AL (P = 0.03). The median value (interquartile range) of TLC (×106/dL) was 8,450 (4,100 – 27,950), with blast counts in peripheral smears at 59 (24 – 80), and in bone marrow aspirates (BMAs) at 95 (75 – 98). There was a significant association (P < 0.001) and a strong association (C = 0.9110) between the morphology of BMA with immunophenotype. Based on immunophenotype, AL was categorized into four groups: B-cell acute lymphoblastic leukemia (B-ALL) (51.5%), T-cell acute lymphoblastic leukemia (T-ALL) (10.3%), AML (22%), and mixed phenotype AL (MPAL) (16.2%). Furthermore, eight subgroups were identified: B lineage, Ia-Common-B-ALL (88.6%) and Ib-Pre-B-ALL (11.4%); T-lineage, IIa-Cortical T-ALL (71.4%) and IIb-Pre-T-ALL (28.6%); AML subgroups, IIIa-M2 (73.93%) and III-M4 (26.7%); and MPAL subgroups, IVa-aberrant expression of myeloid antigens in B-ALL (90.9%), and IVb-aberrant expression of lymphoid markers in AML (9.1%). A poor prognostic immunophenotype (T-ALL, AML) was significantly (P = 0.023) more prevalent in deceased patients with AL. The highest mortality rate was observed in AML (86.4%), followed by T-ALL (57.2%). The most common immunophenotype observed was Common-B-ALL in childhood AL, and a poor prognostic immunophenotype (T-ALL and AML) with the highest mortality rate was found in AML. Thus, knowledge about clinicohematological and immunophenotypic patterns will aid in patient management.

Overcoming post-transplant graft failure and adenovirus infection in a patient with FLT3-TKD-mutated mixed-phenotype acute leukemia: A case report.

Mixed-phenotype acute leukemia (MPAL) with FLT3-TKD mutations is a rare and challenging subtype of leukemia. Effective management strategies are crucial for improving patient outcomes. A 31-year-old man with FLT3-TKD-mutated MPAL achieved hematological remission through the JALSG ALL202-O protocol and gilteritinib, followed by cord blood transplantation (CBT). Post-transplant complications included adenovirus-induced hemorrhagic cystitis, managed with bladder irrigation and ribavirin, and engraftment failure, necessitating a second CBT on Day 35. Subsequent adenoviral conjunctivitis resolved with vidarabine. The patient achieved neutrophil engraftment by Day 76 and was discharged on Day 173 without relapse. This case highlights the importance of vigilant supportive care and tailored therapy in managing MPAL with FLT3 mutations, especially in the context of post-transplant complications.

Cytogenetic and molecular features of mixed-phenotype acute leukemia in US veterans and its potential impact on therapy.

e18535 Background: Mixed phenotype acute leukemia (MPAL) is a rare and heterogeneous subtype of acute leukemia. Per the 2022 WHO criteria, it is categorized based on its predominant immunophenotypic lineage (B vs. T) and the presence of a Philadelphia chromosome (Ph+) or a KMT2A rearrangement. While many other cytogenetic and molecular abnormalities have been described, due to the rarity of this disease, neither their incidence nor the role of targeted therapies has been well defined. We conducted a retrospective study of all veterans with MPAL diagnosed between 2000-2023 to examine the impact of different clinical, immunophenotypic, cytogenetic, molecular, and treatment strategies on overall survival (OS). Methods: Electronic medical record data from the Veterans Affairs Informatics and Computing Infrastructure database were used to identify 320 patients diagnosed with MPAL between 2000-2023 using the text utilization integration feature to query all notes. All patient charts were reviewed manually. Pathology reports and clinical notes were reviewed to collect data on diagnosis, treatment, and outcome. To date, 74 patients have been identified and included in this preliminary analysis. Cox regression analyses were used to compare OS between patients with different MPAL subtypes, cytogenetic, and molecular features as well as different treatment approaches. Multivariate analysis was performed with controls for age, race, and BMI. Results: In line with prior research, decreases in OS were seen among older patients > 65 yo compared to patients <30 yo and those who received an AML induction over ALL induction regimen with HR of 8.28 (p 0.04) and 2.02 (p 0.03) respectively. Patients who had a transplant had significantly improved OS with a HR of 0.19 (p <0.001). Of the 32 patients who had potentially targetable mutations, 14 received targeted maintenance therapy with either Ph+ or FLT3 inhibitors. Patients who got targeted maintenance therapy (including FLT3 inhibitors) had an OS of 55 months compared to 17 months for those who did not. 50% of those patients who did not get maintenance therapy went to transplant and 31% of patients who did get maintenance therapy went to transplant yet these patients still had improved OS. Conclusions: This preliminary data demonstrate that while MPAL is a complex and heterogeneous disease, a significant portion of patients have targetable mutations. Further studies evaluating targeted therapies such as FLT3, IDH, and menin inhibitors in MPAL patients may be warranted. [Table: see text]

Hematopoietic stem cell transplant for adults with mixed phenotypic acute leukemia.

6517 Background: Mixed phenotype acute leukemia (MPAL) is a rare acute leukemia subtype characterized by expression of lymphoid and myeloid lineage markers on blasts. Consequently, the role of hematopoietic stem cell transplant (HCT) consolidation is unclear. We conducted a retrospective study of MPAL patients treated at our institution integrating the impact of transplant status, chemotherapy, and initial response on survival. Methods: We evaluated patients with MPAL at Fred Hutchinson Cancer Center from 1/2005 – 9/2022, some of whom were previously reported (Huang et al, ASH 2023). Independent pathology review using 2022 WHO criteria verified MPAL diagnosis. Potentially transplant eligible patients were defined as those <75 years of age, diagnosed at least 6 months prior to data retrieval date, and alive 100 days after diagnosis with an evaluable induction response. Log-rank and Cox proportional hazard models were used to compare survival and adjust for baseline covariates. Survival was landmarked at 100 days. Results: Of 55 total patients, 42 were potentially HCT eligible and 30 received HCT (71.4%; 20/30 myeloablative). Patients who did not complete HCT were similar in age (median 46.2, range 18-70 vs median 50.3, range 24 – 74, p = ns) and had similar ECOG (ECOG 0-1 86.6% vs 75.0%, p = ns) at diagnosis. Nine of 12 non-transplanted patients had age-adjusted HCT-CI score ≤ 3. Patients receiving a HCT had better progression free survival (PFS) (p = 0.025) and were more likely to be alive at 48 months (61.6% vs. 32.4%, p = 0.011) with a median overall survival (mOS) of not reached (NR) (95% CI, 43 months – NR) compared to a mOS of 13 months (95% CI, 9 months – NR) for those not transplanted. Given that our prior work showed that the type of induction chemotherapy did not influence OS (p = 0.40) or remission status (p = 0.16) (Huang et al. ASH 2023), we investigated impact of remission status at the time of transplant. Differences in PFS and OS persisted when stratifying patients by induction response status with HCT status (PFS p = 0.0048; OS p < 0.0001). Patients who had a complete response (CR) followed by HCT had the longest mOS = NR (17 of 24 patients alive after 48 mo). Patients who had resistant disease (RD) and completed HCT had mOS = 43 months (95% CI, 43 months– NR). Patients who achieved CR but did not undergo HCT had mOS = 19 months (95% CI, 11 months – NR). Patients who had RD and did not undergo HCT had median OS of 6 months (95% CI, 6 – NR). The hazard ratio for death among patients who underwent HCT was 0.28 (95% CI 0.077 – 0.99, p = 0.049). Conclusions: HCT consolidation was significantly correlated with improved survival (p = 0.011). While potentially biased by selection and limited by small sample size, patients benefitted from undergoing a HCT regardless of response to prior therapy (p < 0.0001). This study suggests that patients with MPAL in CR after induction chemotherapy as well as those with less than complete responses should be considered for HCT consolidation.

Mixed-phenotype (B-lymphocytic/myeloid) acute leukemia with ETV6-ABL1 expression.

Mixed-phenotype acute leukemia (MPAL) is rare in the clinic, accounting for approximately 2%-5% of acute leukemia cases. In this study the cohort included 126 patients, of which 125 cases were from re-examined published data and current patients from Shenzhen Longhua District Central Hospital, carrying an ETV6-ABL1 rearrangement from April 15, 2020 to December 19, 2020. The ETS variant transcription factor 6-Abelson proto-oncogene 1 (ETV6-ABL1) fusion gene is mainly seen in malignant hematological diseases such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myeloproliferative neoplasms (MPNs). Positivity of both MPAL and ETV6-ABL1 suggest a poor prognosis. This is the first report of B lymphocytic/myeloid mixed-phenotype acute leukemia with ETV6-ABL1 fusion gene positivity. Complete remission was achieved with chemotherapy for lymphoid and myeloid leukemia and targeted therapy with tyrosine kinase inhibitors (TKIs). The level of ETV6-ABL1/ABL decreased from 23.056% to 11.165%. After consolidation chemotherapy, the patient underwent allogeneic hematopoietic stem cell transplantation but died due to intestinal rejection. There are 126 cases of ETV6-ABL1 fusion gene transcript expression in numerous hematologic malignancies reported to date, including 48 cases of ALL, 12 of AML, and 65 of MPN. Eosinophilia is a common characteristic, especially in MPN patients. Survival analysis suggests that the survival time of ALL and MPN patients receiving TKI treatment is better than that of patients not receiving this treatment. Dasatinib or nilotinib, especially the former, is more effective than imatinib for MPN.

A hybrid protocol CLAG-M, a possible player for the first-line therapy of patients with mixed phenotype acute leukemia. A Polish Adult Leukemia Group experience.

Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the "know-how" of MPAL is based only on retrospective analyses performed on small groups of patients. In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed. Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16-24) and 17 days (range, 12-24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes. CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.

Immunophenotypic but Not Genetic Changes Reclassify the Majority of Relapsed/Refractory Pediatric Cases of Early T-Cell Precursor Acute Lymphoblastic Leukemia.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) develops from very early cells with the potential for both T-cell and myeloid differentiation. The ambiguous nature of leukemic blasts in ETP-ALL may lead to immunophenotypic alterations at relapse. Here, we address immunophenotypic alterations and related classification issues, as well as genetic features of relapsed pediatric ETP-ALL. Between 2017 and 2022, 7518 patients were diagnosed with acute leukemia (AL). In addition to conventional immunophenotyping, karyotyping, and FISH studies, we performed next-generation sequencing of the T-cell receptor clonal repertoire and reverse transcription PCR and RNA sequencing for patients with ETP-ALL at both initial diagnosis and relapse. Among a total of 534 patients diagnosed with T-cell ALL (7.1%), 60 had ETP-ALL (11.2%). Ten patients with ETP-ALL experienced relapse or progression on therapy (16.7%), with a median time to event of 5 months (ranging from two weeks to 5 years). Most relapses were classified as AL of ambiguous lineage (n = 5) and acute myeloid leukemia (AML) (n = 4). Major genetic markers of leukemic cells remained unchanged at relapse. Of the patients with relapse, four had polyclonal leukemic populations and a relapse with AML or bilineal mixed-phenotype AL (MPAL). Three patients had clonal TRD rearrangements and relapse with AML, undifferentiated AL, or retention of the ETP-ALL phenotype. ETP-ALL relapse requires careful clinical and laboratory diagnosis. Treatment decisions should rely mainly on initial examination data, taking into account both immunophenotypic and molecular/genetic characteristics.

Clonotypic VDJ Rearrangements in Mixed Phenotype Acute Leukemia can be Successfully Utilized to Track Minimal Residual Disease.

Multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) can both be used to identify a neoplastic clonotype by targeting CDR3 and assessing rearrangements in IgH, IgK, IgL, TCR-β, and TCR-gamma loci. The clonotypic sequence can be robustly used to track minimal residual disease (MRD). The ability to track MRD by NGS in mixed phenotype acute leukemia (MPAL) is unknown and warrants investigation. Institutional Review Board (IRB) approval was obtained. Central Moffitt Cancer Center (MCC) database was searched to locate any patients with MPAL from over 600,000 entries. Patient charts were manually curated to identify those with clonoSEQ data, and clinical data was procured from the electronic medical record (EMR). Twenty-nine patients with MPAL were identified. Only 2 patients with clonoSEQ testing were found. Both demonstrated a B/myeloid phenotype, and both were bilineal. NGS (clonoSEQ) identified 4 dominant (IGH) (patient A; 8/2019) and 2 dominant sequences (patient B; 10/2019), respectively. In both patients, clonoSEQ testing successfully tracked minimal residual disease and mirrored clinical disease burden. This report is the first to confirm the utility of NGS-based MRD tracking in patients with MPAL and shows increased sensitivity of NGS over MRD flow cytometry.

Clinical features of immature leukemias in children.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), mixed phenotypic acute leukemia (MPAL), and acute myeloid leukemia with minimal differentiation (AML-M0) all originate from immature hematopoietic progenitor cells and have a poor prognosis. We investigated the clinical characteristics of these immature leukemias in 17 children (ETP-ALL: 8, MPAL: 5, AML-M0: 4) at seven institutions. Clinical and laboratory findings were comparable across disease types. Eleven and six patients received ALL- and AML-oriented induction chemotherapy, with six and four achieving complete remission (CR), respectively. Five additional patients achieved CR after salvage with the other type of chemotherapy. Eight patients received hematopoietic cell transplantation (HCT) in first CR, and six survived without relapse. However, six of seven patients who did not receive HCT during first CR relapsed; all underwent HCT later, and only three survived. The 5-year event-free survival (EFS) and overall survival (OS) rate were 37% and 69%, respectively. Patients who achieved CR after induction chemotherapy and received HCT in first CR had favorable EFS and OS. Notably, all patients who received HCT in first CR survived 5years after diagnosis. Appropriate induction chemotherapy and HCT in first CR could improve the outcome of immature leukemias.

Association between direct acting agents used for chronic hepatitis C virus infection and the occurrence of acute leukaemia – A disproportionality analysis

BACKGROUND AND AIMSA recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection. METHODSWe conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal. RESULTSWe identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n = 17) and 39% (n = 9) of cases. The events reported were AML (n = 22), ALL (n = 11), AML and ALL (n = 1) and UAL (n = 15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL. CONCLUSIONThis study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.

Clinicopathological and Immunophenotypic Characteristics of Series of ZNF384 Re-arranged Acute Leukemias.

Rearrangement involving ZNF384 gene (ZNF384-r) is recently being described in acute leukemias. We present the clinic-pathological and immunophenotypic findings in a series of five cases of acute leukemia with ZNF384-r reported in our Institute between September 2020 to September 2023. Notably, while TCF3::ZNF384 fusion was the most frequently encountered abnormality, the fusion partner was not identified in two patients with ZNF384-r BCP-ALL. Immunophenotypically, patients presenting as B-cell precursor acute lymphoblastic leukemia (BCP-ALL) had a distinct profile characterized by weak or absent CD10 expression and the presence of myeloid markers such as CD13/CD33. Our findings underscore the importance of recognizing the distinct immunophenotypic features of ZNF384-r leukemias, particularly in cases presenting with atypical BCP-ALL or B/Myeloid mixed phenotype acute leukemia phenotypes. Moreover, these findings highlight the necessity for tailored diagnostic algorithms in clinical laboratories to facilitate the timely and accurate diagnosis of this clinically relevant leukemia subtype.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with BCR::ABL1 fusion.

BCR::ABL1 fusion is found in<1% of de novo acute myeloid leukemia (AML) cases and confers a poor prognosis. This Japanese nationwide survey analyzed patients with AML (n=22) and mixed phenotype acute leukemia (MPAL) (n=10) with t(9;22) or BCR::ABL1 who underwent allogeneic hematopoietic cell transplantation (allo-HCT) between 2002 and 2018. The 3-year overall survival (OS) rates were 81.3% and 56.0%, respectively (p=0.15), and leukemia-free survival (LFS) rates were 76.2% and 42.0%, respectively (p=0.10) in patients with AML and MPAL. The relapse rates were 9.5% and 14.0% (p=0.93), and the non-relapse mortality (NRM) rates were 14.3% and 44.0%, respectively (p=0.10) in patients with AML and MPAL. One in 17 patients with AML, with pre-transplant tyrosine kinase inhibitors (TKI), and three in five patients with AML, without pre-transplant TKI, did not achieve complete remission (CR) before allo-HCT (p=0.024). Among the 20 patients with known disease status after allo-HCT, 95.0% were in hematological or molecular CR. None of the four patients who received post-transplant TKI for prophylaxis or measurable residual disease relapse experienced hematological relapse. In conclusion, our results suggest that pre-transplant TKI could improve disease status before allo-HCT. Moreover, allo-HCT resulted in high OS, high LFS, low relapse, and low NRM rates in patients with AML with BCR::ABL1.